SUMMARY Alzheimer's disease (AD) is the most common form of dementia in the elderly, manifesting progressive neurodegenerative conditions including amyloid plaque and neurofibrillary tangle formation, and cognitive impairment. Genetic inheritance is estimated to determine nearly 80% of the AD cases. Besides the well-known familial mutations in APP, PSEN1 and PSEN2 genes found in early-onset AD cases, over 30 loci or genes are associated sporadic late-onset AD (LOAD) as indicated by recent genome-wide association studies and whole exosome/genome sequencing projects. APOE and PICALM are among the top of the list. APOE encodes the lipid carrier apolipoprotein E protein. Among its three major isoforms (?2, ?3, and ?4), ?3 is the most common isoform, ?4 is unarguably the strongest genetic risk factor for LOAD, and ?2 is the less frequent but is protective for AD. These isoforms also differentially affect molecular and cellular events that are important for amyloid ? (A?) metabolism and neurodegeneration. On the other hand, PICALM encodes the phosphatidylinositol binding clathrin assembly protein, and is confirmed by nearly all GWAS studies as a major AD-associated gene. PICALM controls receptor internalization and subsequent intracellular trafficking of clathrin-coated vesicles. It plays key roles in mediating brain clearance of A?, regulating activities of ?- and ?-secretases for A? production, mitigating A? toxicity in neurons, and promoting Tau clerance via autophagy. More interestingly, the unique genetic interaction between APOE and PICALM in AD has been demonstrated based on population studies, as PICALM genotypes at multiple AD-associated confer risk predominantly in ?4 carriers, and AD risk PICALM rs3851179G allele and APOE ?4 allele synergistically affect cortex volume and working memory function in AD patients. However, the mechanism underpinning this interaction in AD is still unknown. Based on the PICALM's interactome and functions in maintaining cell surface protein functions, as well as our preliminary findings showing impaired APOE lipidation and reduced level of surface ABCA1 cholesterol and phospholipid transporter in PICALM deficient mice, we hypothesize that PICALM may facilitate APOE lipidation and A? metabolism by controlling the function of ABCA1 transporter, and therefore risk PICALM rs3851179G and APOE ?4 alleles adversely affect AD pathogenesis. To test this hypothesis, we propose to: i) determine the cellular and molecular mechanisms of PICALM in facilitating APOE lipidation and characterize PICALM- dependent internalization and trafficking of ABCA1 transporter (AIM 1); ii) explore the functional impact of PICALM and APOE's synergistic interaction in vivo on neurodegenerative phenotypes (AIM 2). We expect to gather first-hand evidence that the risk alleles of two genes synergistic influence AD pathogenesis, and establish the molecular and cellular mechanisms of interaction between APOE and PICALM both in vitro and in vivo. The outcomes of the studies will provide new insights into the inheritability, etiology and pathogenesis of AD, and serve as a foundation for future studies to therapeutically target this interaction for AD diagnosis and treatment.